Download Diagnostic Characteristics of Clozapine

Diagnostic Trends in Clozapine-Induced Myocarditis
Diagnostic Characteristics of Clozapine-Induced Myocarditis
Identified by an Analysis of 38 Cases and 47 Controls
Kathlyn J. Ronaldson, MSc, DPhil; Andrew J. Taylor, MBBS, FRACP, PhD;
Paul B. Fitzgerald, MBBS, MPM, FRANZCP, PhD;
Duncan J. Topliss, MBBS, FRACP, MD, FACE;
Maros Elsik, BSc (Med), MBBS, FRACP;
and John J. McNeil, MBBS, FRACP, MSc, PhD, FAFPHM
Objective: To analyze cases of clozapineinduced myocarditis for clinical and diagnostic
trends.
Method: A case definition was developed by
a multidisciplinary group using reports of myocarditis with clozapine submitted to the Australian
Therapeutic Goods Administration. The definition
uses for diagnosis either histology or the combination of new signs of cardiac dysfunction combined
with a cardiac-specific diagnostic parameter occurring within 45 days of starting clozapine. Potential
cases of clozapine-related myocarditis occurring
between January 1993 and September 2008 and
a comparative group of long-term clozapine users were documented from the patients’ medical
records.
Results: Thirty-eight of 59 reviewed cases met
the case definition. Three patients died, and the
diagnosis for these was confirmed on cardiac histology. Nearly all of the remaining patients had
persistent tachycardia and elevated troponin level.
The time to onset was 14–22 days in all except 2
patients. Of the patients who survived, 66% (23
cases) had eosinophilia occurring 0–7 days (mean,
4.0) after the peak in troponin. C-reactive protein
(CRP) level was elevated to above 100 mg/L (952
nmol/L) in 79% (23 cases), and some had elevated
levels of CRP when troponin level was still normal.
None of the control group (47 patients) met the
case definition.
Conclusions: Eosinophil counts should not be
relied on for diagnosis of clozapine-related myocarditis, but elevated CRP may be an early indicator
of developing myocarditis. Patients starting clozapine should be actively monitored for myocarditis
during the first 4 weeks, with extra care taken
during week 3.
J Clin Psychiatry
© Copyright 2010 Physicians Postgraduate Press, Inc.
Submitted: January 7, 2009; accepted March 6, 2009.
Online ahead of print: March 9, 2010 (doi:10.4088/JCP.09m05024yel).
Corresponding author: Kathlyn Ronaldson, MSc, DPhil, Department of
Epidemiology and Preventive Medicine, Monash University, The Alfred
Hospital, Melbourne, Victoria 3004, Australia
([email protected]).
J Clin Psychiatry
I
n 1999, the publication by Kilian et al1 of an Australian
case series of myocarditis with clozapine provided strong
evidence that this relationship was causal, especially given
the estimated high incidence of 1 in 500 in the first month
of clozapine use. This evidence was reinforced 18 months
later by a data-mining study conducted on the international
database of adverse drug reactions maintained by the World
Health Organization.2 In this study, Coulter et al2 found
that clozapine was significantly more frequently associated
with myocarditis than any other drug. In subsequent publications,3,4 it has been proposed that the incidence may be
more than 2% of patients starting clozapine.
Clozapine is recognized as the most effective antipsychotic available for treatment-resistant schizophrenia,5,6
but its use is limited to third-line therapy because of its
adverse reactions, including agranulocytosis, neutropenia,
and myocarditis. Mandatory full blood count monitoring is
effective in reducing the incidence of agranulocytosis, but
despite introduction by the sponsor of a cardiac monitoring
program in Australia in December 1999, the occurrence of
clozapine-related myocarditis and death from this cause has
not been prevented.
With the exception of a case series3 from Queensland,
the publications to date either have been individual case
reports7–16 or have described cases collected through a
national spontaneous adverse drug reactions reporting
program.1,17–21 Published cases have not adhered to a common single case definition, or any case definition at all.
Hence, published reports provide a rough guide but not a
reliable indicator of clinical and diagnostic trends to assist
in monitoring and diagnosis. Because of the potential risk
of serious cardiac damage with myocarditis and death from
arrhythmia and other complications in the acute phase, it
is important to make the diagnosis as early as possible to
enable timely drug withdrawal; conversely, because of the
often unique benefit of the drug, the diagnosis should not
be assumed without reliable evidence.
Because of the clinical need to characterize clozapine­associated myocarditis further, we developed and validated
a case definition. On the basis of this definition, we documented 38 cases from the patients’ medical records and
e1
Ronaldson et al
analyzed them for trends in clinical and diagnostic
parameters.
METHOD
A case definition (Table 1) that maximizes specificity at
the expense of sensitivity was developed by a multidisciplinary group, including individuals with specialist expertise
in cardiology, pharmacology, pharmacovigilance and epidemiology using 116 reports of myocarditis submitted to the
Australian Therapeutic Goods Administration.
For the case analysis, cases of clozapine-related myocarditis were identified from reports submitted to the Therapeutic
Goods Administration between January 1993 and September
2008, from cases advised directly to the researchers, and
from cases in the National Coroners’ Information Service
database. A comparative group comprised patients starting
clozapine close in time to a case occurring at the same health
service. These patients had taken clozapine for at least 6
months without manifest cardiac disease.
Documentation of each patient included the date of birth,
sex, clozapine start and end dates, dose of clozapine taken
each day, baseline pathology results and results obtained
during the course of clozapine treatment and until resolution of myocarditis for the cases, and signs and symptoms
recorded in the progress notes. Documentation for each case
was reviewed by the study steering group for compliance
with the case definition for clozapine-related myocarditis
(see Table 1).
Approval for the study was obtained from the Human
Research Ethics Committees of the following institutions or
health services: Monash University, Barwon Health, Bayside
Health, Bendigo Health, Department of Human Services,
Department of Justice, Eastern Health, Mercy Health, North
West Mental Health, Peninsula Health, Southern Health (all
from Victoria, Australia); and, Northern Sydney Central
Coast Health (from New South Wales, Australia). The approvals covered access to medical records without patient
consent. In addition, an Access Agreement was signed with
the Victorian Institute of Forensic Medicine for access to
the National Coroners’ Information Service database and
a Deed of Confidentiality and Conflict of Interest with the
Therapeutic Goods Administration for access to original
case reports.
RESULTS
Compliance With the Case Definition
Of 59 cases reviewed, 38 met the case definition. Three
cases were fatal and for these the diagnosis was made by
cardiac histology at autopsy. For the remaining 35 cases, the
clinical criteria for myocarditis were met by the presence
of documented sustained tachycardia in 32 cases and by
basal lung crepitations and/or peripheral edema in 3 cases.
In 30 cases, the cardiac specific diagnostic parameters were
e2
Table 1. Case Definition for Clozapine-Related Myocarditis
Onset of new symptoms within 45 days of commencing clozapine
PLUS
Histologic evidence of myocarditis at postmortem or on myocardial
biopsy in the absence of other plausible explanations, including
Confirmed viral infection or
Exposure to other likely causative agents within an appropriate
timeframe
OR
New signs of cardiac dysfunction (eg, persisting tachycardia [heart
rate > 100 bpm for ≥ 24 hr], third heart sound, basal crepitations,
peripheral edema) with, or without, febrile systemic illness
PLUS
At least ONE of the following diagnostic abnormalities with or
without eosinophilia:
Elevated troponin I and/or troponin T levels (≥ 2 times the upper
limit of normal)
Elevated CK-MB levels (≥ 2 times the upper limit of normal)
Evolutionary electrocardiographic changes (involving ≥ 1 mm ST
segment depression or T wave inversion in 2 or more
contiguous leads, excluding lead aVR) consistent with
myocarditis, with no other obvious cause
Chest X-ray evidence of heart failure
Evidence of left or right ventricular systolic dysfunction by
echocardiogram, gated pool blood scan, magnetic resonance
imaging, or contrast ventriculogram
Magnetic resonance imaging diagnostic of myocarditis
In the absence of alternative plausible etiologies:
Confirmed viral infection
Exposure to other likely causative agents within an appropriate
timeframe
Other likely explanation for these findings, including
Acute myocardial infarction
Neuroleptic malignant syndrome
Pneumonia or other pulmonary infection
Pulmonary embolism
Other (eg, severe sepsis)
Of these other likely explanations, only confirmed myocardial
infarction and neuroleptic malignant syndrome, in the absence
of histologic evidence of myocarditis, were automatic exclusions.
The presence of the other named alternative diagnoses required
documentation consistent only with myocarditis and not with the
other diagnosis.
Abbreviations: aVR = limb lead augmented vector right, bpm = beats per
minute, CK-MB = creatine kinase-MB.
satisfied by at least 1 troponin I or T measurement greater
than or equal to twice the upper limit of normal. In each of
these cases, the patient had a documented normal troponin
level at baseline. The 5 cases without raised troponin level
had diagnostic confirmation by evidence of left ventricular
impairment by echocardiography (4 cases) or gated blood
pool scan (1 case). In 1 patient, the diagnosis of myocarditis
was confirmed by magnetic resonance imaging.22
Twenty-one potential cases were excluded for the following reasons: the time to onset was more than 45 days (3
cases), other disease states may have caused confounding
(4 cases), insufficient data were available to make an assessment (2 cases), or the clinical and diagnostic criteria were
not met by the data (12 cases).
Characteristics of the Cases
The characteristics of the confirmed cases are presented in Table 2 and the diagnostic features in Table 3.
J Clin Psychiatry
Diagnostic Trends in Clozapine-Induced Myocarditis
Table 2. Characteristics of the 38 Cases
Characteristic
Value
Range
Outliers
Gender, n
Male
27
Female
11
22–73
Age, y
38 ± 13a
Duration of clozapine, db
17.6 ± 2.3a
14–22
26 and 33
Dose at onset, mg/d
232 ± 69a
100–400
50c and 750
Outcome, n
Fatal
3
Survived
35
a
Mean ± SD.
b
Duration of clozapine used as a surrogate for time to onset of
myocarditis.
c
The dose had been reduced from 100 mg/d with the onset of illness.
Table 3. Diagnostic Features of the 38 Cases of Myocarditis
No. of Cases
Parameter
Present
Absent
Unknown
34
4
0
Tachycardia (heart rate > 100 bpm)a
Heart rate ≥ 120 bpm
30
8
0
Fever (> 37°C)
33
5
0
Chest pain
22
16
0
Troponin I/T level ≥ 2ULN
31
5
2
Left ventricular impairment by
22
8
8
cardiac imaging
ECG abnormalities
29
7
2
T-wave abnormalities
27
9
2
ST-elevation/depression
14
22
2
CK-MB level > ULN
2
5
31
Creatine kinase level > ULN
11
25
2
Eosinophil count > ULN
23
12
3b
Eosinophil count ≤ 0.1 × 109/L
6
29
3b
C-reactive protein level > 100 mg/L
23
6
9
ESR > 50 mm/hr
7
7
24
White blood cell count > ULN
22
16
0
Neutrophil count > ULN
27
11
0
Monocyte count > ULN
12
26
0
a
Persistent for ≥ 24 hours.
b
Data missing for 3 fatal cases.
Abbreviations: bpm = beats per minute, CK-MB = creatine kinase-MB,
ECG = electrocardiogram, ESR = erythrocyte sedimentation rate,
ULN = upper limit of normal.
Echocardiography (29 cases) or gated blood pool scan (1
case) was performed 0–5 days after stopping clozapine. Of
these 30 patients, 22 had left ventricular impairment with
ejection fraction ranging from the lower limit of normal to
30%. All except 2 of 18 cases with baseline echocardiography had deterioration in cardiac function from baseline.
Two patients, 1 of whom died, had no symptoms associated with myocarditis. Eighteen patients had persistent fever
for up to 6 days before troponin was found to be elevated
or other diagnostic measures indicated myocarditis. Several
of these had normal troponin after onset of fever. Other
symptoms associated with myocarditis were sore throat,
vomiting, diarrhea, headache, dyspnea, and neck pain. The
variety in clinical presentation is illustrated by the 5 case
histories in Table 4.
Peripheral eosinophilia developed in 66%23 of the nonfatal cases (see Table 3), but a notable feature was a delay in
J Clin Psychiatry
Table 4. Case Vignettesa
Case 1: The heart rate of a patient rose to 133 (baseline 100) bpm after 16
days of clozapine. Troponin I level was not raised above normal, but
echocardiography showed deterioration in ejection fraction from a
baseline of > 59% to 40%–59%. CRP rose to a maximum of 190 mg/L
Case 2: A patient died while asleep after taking clozapine (current dose
750 mg/d) for 33 days. Hypersensitivity myocarditis was diagnosed by
histology at autopsy. Although the patient had been hospitalized from
the time of starting clozapine, there had been no indication of physical
illness. Weekly blood tests were due the following day
Case 3: A patient developing a fever with tachycardia of 120 bpm after
17 days of clozapine had normal troponin the following day, although
CRP was elevated to 113 mg/L. Another normal troponin level was
followed by an elevated value on day 21. Myocarditis was further
confirmed by echocardiographic evidence of new left ventricular
dysfunction
Case 4: After taking clozapine for 20 days, a patient had basal
crepitations but only brief periods with a heart rate of 100 beats/
min or more. Troponin I level was 5.6 µg/L (ULN 0.5), CRP 224
mg/L, creatine kinase 587 U/L and left ventricular ejection fraction
20%–39%. Pulmonary embolism, bacterial infection, and neuroleptic
malignant syndrome were investigated and excluded
Case 5: A patient developed a sore throat, stiff joints, neck pain,
fever, tachycardia, and chest pain on clozapine day 15. Despite the
indications of neuroleptic malignant syndrome, creatine kinase was
not elevated; maximum recorded was 61 U/L. Further, no infectious
cause was identified. Troponin was 0.11 µg/L (ULN 0.03); CRP, 475
mg/L; and left ventricular ejection fraction, 30%–35%
a
Age and gender are not provided to protect the identity of the
individuals.
Abbreviations: bpm = beats per minute, CRP = C-reactive protein,
ULN = upper limit of normal.
the increase in eosinophil count, with the peak occurring
from 0 to 7 days (mean ± SD, 4.0 ± 2.2) after the maximum
observed troponin I or T value. Because of this delay, none
of the fatal cases developed eosinophilia. In 5 instances,
C-reactive protein (CRP) level was above 50 mg/L (476
nmol/L), while troponin level was still normal. In a further 9 cases, the first CRP determination was more than
150 mg/L on the day troponin level was first found to be
elevated.
Case Recovery
Except for the fatal cases and 1 who appeared well
throughout, all identified cases of clozapine-associated
myocarditis experienced improvement in constitutional
symptoms following withdrawal of clozapine. Recovery
was reflected by return of heart rate to less than 100 beats
per minute (29 cases) and a fall in troponin level to normal
(25 cases) or an incomplete reduction (3 cases). All except
1 of the 35 nonfatal cases had documented return of either
heart rate or troponin levels to within the normal range.
The exception had a fall in troponin I level to half of the
maximum with no further determinations.
Follow-up cardiac imaging more than 5 days after clozapine cessation was available for 17 cases: 12 showed
normal cardiac function, 4 showed improvement, and 1
was unchanged. The patient without improvement 7 days
after stopping clozapine nevertheless had normalization of
heart rate and troponin level.
e3
Ronaldson et al
Table 5. Diagnostic Features of the Comparative Group of 47
Patients Who Took Clozapine for ≥ 6 Months Without Manifest
Cardiac Disease
Figure 1. Percentage of Cases and Controls With Each of 5
Diagnostic Characteristics
No. of Patients
Parameter
Present Absent Unknown
Tachycardia (heart rate > 100 bpm)a
26
6
15
Heart rate ≥ 120 bpm
12
20
15
Fever (> 37°C)
6
13
28
Chest pain
1
46
0
Troponin I/T level > ULN
0
20
27
(clozapine days 12–21)
Eosinophil count > ULN
14
30
3
(clozapine days 14–28)
Left ventricular impairment by cardiac
0
28
19
imaging after clozapine day 45
C-reactive protein level > 50 mg/L
1
6
40
a
One or more episodes; no limit on duration.
Abbreviations: bpm = beats per minute, ULN = upper limit of normal.
100
80
70
%
60
50
40
30
20
10
0
Comparative Group
Forty-seven of 69 patients reviewed met the criteria for
the comparative group. These 47 patients were aged 19–73
years (mean ± SD, 37 ± 13), and 32 were male and 15 female.
Table 5 presents the results of investigations relevant to the
exclusion or diagnosis of myocarditis in this group, and Figure 1 compares the rates of 5 features for cases and controls.
The odds ratio for eosinophilia 14–28 days after starting
clozapine for cases with myocarditis versus the comparative
group was 3.29 (95% CI, 1.21–9.02; P = .009). The sensitivity of eosinophilia for a diagnosis of myocarditis was 61%
and specificity, 68%. Eight control patients had both eosinophilia and tachycardia.
DISCUSSION
Study Strengths
A number of factors of the Australian context have allowed us to obtain detailed documentation of the initiation
of clozapine for both the cases and the controls and for the
clinical presentation of myocarditis in the patients in whom
it developed. Clozapine is typically initiated in a hospital,
with close monitoring of the patient’s vital signs, minor
side effects, as well as hematologic and cardiac parameters.
Much of the literature about clozapine-related myocarditis
has been generated from Australia, and it is well recognized
in this country. The well supported adverse reaction monitoring system has led to reports being accumulated from
across Australia and has in turn generated added awareness
of this serious adverse effect.
This is the first study to systematically document multiple cases of clozapine-induced myocarditis from patient
medical records. Clozapine initiation commonly causes
a variety of minor signs and symptoms, some of which,
including tachycardia, eosinophilia, and fever, may confound the diagnosis of myocarditis. We have established a
case definition that distinguishes between myocarditis and
these other benign conditions, as demonstrated by none
e4
Cases
Controls
90
a
HR > 100
bpm
HR ≥ 100
bpm
Fever
Eosinophilia Chest Pain
Cases in which the patient died were included in the category of no
eosinophilia.
Calculations for controls excluded those for whom data were missing,
meaning that the denominator changed with each calculation.
b
of the comparative group meeting the case definition. The
suitability of the case definition is further supported by
the rapid recovery of the surviving cases in this group following withdrawal of clozapine. From this foundation, we
have been able to examine cases of myocarditis and identify
clinical characteristics of myocarditis that can inform monitoring and early diagnosis in the future.
Time to Onset
This analysis has used the duration of clozapine as a surrogate for the time to onset, and the duration of clozapine
in 36 of 38 cases was 14–22 days. The possibility of bias
with respect to time to onset of myocarditis in this study
should not be overlooked. All except 1 case were identified
to the researchers because they were recognized by a treating clinician in the first instance. Clinicians are more likely
to recognize cases occurring earlier rather than later in the
course of clozapine because of a heightened level of alertness
to adverse reactions in the early stages of a new treatment,
because of the cardiac monitoring protocol with checks at
days 7 and 14, and because, although most start clozapine
in hospital, few are hospitalized for more than 3 weeks after
initiation. In published cases, the time to onset is typically
7–35 days. It is possible that time to onset is a function of
rate of dose titration, but this is yet to be investigated.
Heart Rate as a Diagnostic Characteristic
It should be noted that tachycardia (heart rate > 100
beats/min) as a diagnostic feature of cases was required to
persist for at least 24 hours. However, when tachycardia
was recorded in a control patient, data on persistence were
usually not available and were not documented. Hence, the
J Clin Psychiatry
Diagnostic Trends in Clozapine-Induced Myocarditis
comparison of frequency of heart rate of more than 100 beats
per minute for cases and controls places a stricter requirement on cases (Figure 1). For the comparison of frequency
of heart rate of 120 or more beats per minute, persistence
was not a criterion for either group.
With regard to the validity of persistence of tachycardia
as a diagnostic feature, it was supported by conjunction
in time with symptoms of illness and the presence of cardiacspecific diagnostic measures, followed by resolution of these,
including tachycardia, on withdrawal of clozapine.
Eosinophil Count, C-Reactive Protein Level, and Fever
A recently published review advises determining eosinophil count as a means to diagnosis of clozapine-related
myocarditis.23 In the present series, 66% of the nonfatal
cases experienced eosinophilia, and, surprisingly, the elevation in eosinophil count was delayed for as long as 7 days
after the peak in troponin I/T levels. Checking for eosinophilia would not assist in the early diagnosis of myocarditis
and, most importantly, would not prevent fatalities. Furthermore, overreliance on peripheral eosinophil count could
result in clozapine withdrawal in a patient without myocarditis, as indicated by the 32% incidence of eosinophilia
in the comparative group.
In contrast, there are indications that CRP may be the
first measurable parameter to herald the onset of a disease
process. While it is a nonspecific inflammatory marker,
elevations above 50 mg/L would be a reason to monitor
the health of the patient more closely, particularly by daily
electrocardiography (ECG) and troponin determinations.
Similar monitoring advice could be associated with the development of fever, and a normal troponin determination
after the development of fever does not mean that myocarditis has been excluded; rather, the fever may be part of an
evolving myocarditis prodrome.
Limitations
A limitation of this case analysis is that it was constrained
by the investigations that the treating clinician of each individual patient chose to conduct. For instance, it was not
possible to fully explore the value of CRP as an early indicator of myocarditis. Similarly, daily eosinophil counts would
have assisted in the characterization of the observed delay
in the development of eosinophilia.
Other Countries
Countries other than Australia, and perhaps New
Zealand,21 have reported very few cases of myocarditis
considering clozapine usage. Various causes have been postulated including genetic differences and high ozone in the
breathed atmosphere of the southern hemisphere.24 A plausible reason, however, is that cases have been missed in other
countries. The presentation of myocarditis is nonspecific.
It may resemble influenza or there may be no symptoms.
Added to this are patient factors, such as psychiatric illness,
J Clin Psychiatry
which typically is poorly controlled at the time of clozapine
initiation, making it difficult for patients to communicate
symptoms they feel. Without a preceding high level of
awareness of the association and hence active investigation
for myocarditis, it very likely will be missed, especially if
clozapine is initiated without the clinical scrutiny inherent
in hospitalization.
A recent analysis25 of data from a health maintenance
organization in the United States found a higher rate of
mortality from sudden cardiac death in community patients
treated with clozapine than with any other antipsychotic.
The study included no data on time to onset, but it is at
least feasible that myocarditis may have contributed to the
excess of deaths.
Monitoring
Not all centers internationally routinely initiate clozapine with the patient hospitalized, but weekly blood count
monitoring is mandatory in several countries (Australia,
Canada, New Zealand, United Kingdom, and United States)
during the first 18 weeks. Diagnosis of myocarditis would
be improved if the collected blood were also used to check
cardiac parameters (troponin I or T) and CRP and an ECG
taken at baseline and at 7, 14, 21 and 28 days. Whether the
patient is treated in the community or as an inpatient, he or
she should be seen by a physician and examined for signs
and symptoms of illness at each of these intervals. Although
chest pain was present in only 58% of cases in this study,
it may be 1 useful indicator. Those with elevated CRP or
indications of illness not conclusively diagnosed as having
another cause should be closely monitored over the next
few days. Further, patients and their carers should also be
advised to report any illness, between the dates of routine
tests, to a physician during this critical 4-week period. If
troponin level is elevated or a new ECG abnormality is detected, clozapine should be discontinued pending further
investigation.
CONCLUSION
In the absence of a gold standard for the diagnosis of
clozapine-associated myocarditis, our case definition is
a simple algorithm that can assist clinicians to identify
clozapine-related myocarditis while excluding those with
benign rises in eosinophil counts and heart rate. This
analysis of 38 cases found that the typical time to onset
of clozapine-related myocarditis is 14–22 days after starting clozapine and that eosinophil counts are a poor tool
for diagnosis. Patients starting clozapine should be actively
monitored for myocarditis during the first 4 weeks, with
extra care taken during week 3. Rises in CRP level and development of fever may be early indicators of myocarditis
and daily ECG and troponin measurements in the presence
of fever or following a CRP level of more than 50 mg/L may
be diagnostically useful.
e5
Ronaldson et al
Drug name: clozapine (FazaClo, Clozaril, and others).
Author affiliations: Department of Epidemiology and Preventive
Medicine, Monash University (Drs Ronaldson, McNeil, and Elsik); and
the Heart Centre (Dr Taylor), Monash Alfred Psychiatric Research
Centre (Dr Fitzgerald), and Department of Endocrinology and Diabetes
(Dr Topliss) the Alfred Hospital, Melbourne, Victoria, Australia.
Potential conflicts of interest: None reported.
Funding/support: A salary was paid to Dr Ronaldson in 2006 and 2007
from a grant from the Australian National Health and Medical Research
Council.
Acknowledgments: The authors are grateful for the assistance of individuals at each of the following health services: from Victoria, Barwon
Health (Dr T. Callaly, Mr W. Kuluris, Ms D. Grapsas), Bayside Health
(Ms K. Hirth, Ms C. Forrester, Ms A. Given, Ms L. Scarff, Ms L. Hughes,
Ms A. La Trobe, Ms J. Giuliani, Mrs D. Elliott), Bendigo Health
(Dr P. Chopra, Ms S. Maynard), Eastern Health (Assoc Prof P. Katz,
Ms J. Jolly, Ms A. McClaren), North West Mental Health (Dr K. Morton,
Ms Gisella Campanelli, Ms A. Hammoud, Ms A. Gilchrist, Mr A. Cox,
Ms H. Manos), Peninsula Health (Assoc Prof R. Newton, Mr G.
Dobson), Southern Health (Dr S. Damodaran, Ms A-M Foster, Ms L.
Rouda, Mr D. Graham, Mr A. Koca), Thomas Embling Hospital (Dr A.
Brennan), and Werribee Mercy Mental Health Service (Dr S. Jespersen,
Assoc Prof D. Stevenson, Mrs K. Hodge, Ms F. Gleeson, Ms K. Gray);
and from New South Wales, Northern Sydney Central Coast Health (Dr
M. Paton, Dr L. Newton, Mr J. Glen, Mr J. Bajuk, Ms A. Steele, Mrs P.
Wheeler).
REFERENCES
1. Kilian JG, Kerr K, Lawrence C, et al. Myocarditis and cardiomyopathy
associated with clozapine. Lancet. 1999;354(9193):1841–1845.PubMed doi:10.6/S4-73(9)85
2. Coulter DM, Bate A, Meyboom RH, et al. Antipsychotic drugs and heart
muscle disorder in international pharmacovigilance: data mining study.
BMJ. 2001;322(7296):1207–1209.PubMed doi:10.36/bmj279
3. Reinders J, Parsonage W, Lange D, et al. Clozapine-related myocarditis
and cardiomyopathy in an Australian metropolitan psychiatric service.
Aust N Z J Psychiatry. 2004;38(11–12):915–922.PubMed doi:10./j4-62018.x
4. Tirupati S. Clozapine and heart in the Hunter region. Aust N Z J
Psychiatry. 2006;40(1):97.PubMed doi:10./j4-620178_.x
5. Freedman R. The choice of antipsychotic drugs for schizophrenia.
N Engl J Med. 2005;353(12):1286–1288.PubMed doi:10.56/NEJMe82
6. Leucht S, Corves C, Arbter D, et al. Second-generation versus firstgeneration antipsychotic drugs for schizophrenia: a meta-analysis.
Lancet. 2009;373(9657):31–41.PubMed doi:10.6/S4-73(8)1X
7. Bandelow B, Degner D, Kreusch U, et al. Myocarditis under therapy
e6
with clozapine. Schizophr Res. 1995;17(3):293–294.PubMed
8. Reid P. Clozapine rechallenge after myocarditis. Aust N Z J Psychiatry.
2001;35(2):249.PubMed doi:10.46/j-208a.x
9. Annamraju S, Sheitman B, Saik S, et al. Early recognition of clozapineinduced myocarditis. J Clin Psychopharmacol. 2007;27(5):479–483.PubMed doi:10.97/jcpb3e8456
10. Pieroni M, Cavallaro R, Chimenti C, et al. Clozapine-induced
hypersensitivity myocarditis. Chest. 2004;126(5):1703–1705.PubMed doi:10.378/chest265
11. Kakar P, Millar-Craig M, Kamaruddin H, et al. Clozapine induced myocarditis: a rare but fatal complication. lnt. J Cardiol. 2006;112(2):e5–e6. doi:10.6/jcar2 3
12. Fineschi V, Neri M, Riezzo I, et al. Sudden cardiac death due to hypersensitivity myocarditis during clozapine treatment. Int J Legal Med.
2004;118(5):307–309.PubMed doi:10.7/s4-61
13. Merrill DB, Ahmari SE, Bradford J-ME, et al. Myocarditis during
clozapine treatment. Am J Psychiatry. 2006;163(2):204–208.PubMed doi:10.76/apj324
14. Varambally S, Howpage P. Acute myocarditis associated with clozapine.
Australas Psychiatry. 2007;15(4):343–346.PubMed doi:10.8/39567401
15. Belloni E, De Cobelli F, Esposito A, et al. Myocarditis associated with
clozapine studied by cardiovascular magnetic resonance. J Cardiovasc
Magn Reson. 2007;9(3):591–593.PubMed doi:10.8/97645
16. Rathore S, Masani ND, Callaghan PO. Clozapine-induced effusoconstrictive pericarditis: case report and review of the literature.
Cardiology. 2007;108(3):183–185.PubMed doi:10.59/6
17. Haas SJ, Hill R, Krum H, et al. Clozapine-associated myocarditis:
a review of 116 cases of suspected myocarditis associated with the
use of clozapine in Australia during 1993–2003. Drug Saf. 2007;30(1):
47–57.PubMed doi:10.265/ 8-73015
18. Hägg S, Spigset O, Bate A, et al. Myocarditis related to clozapine
treatment. J Clin Psychopharmacol. 2001;21(4):382–388.PubMed doi:10.97/4-280 5
19. Degner D, Bleich S, Grohmann R, et al. Myocarditis associated
with clozapine treatment. Aust N Z J Psychiatry. 2000;34(5):880.PubMed doi:10.46/j-208n.x
20. La Grenade L, Graham D, Trontell A. Myocarditis and cardiomyopathy associated with clozapine use in the United States. N Engl J Med.
2001;345(3):224–225.PubMed doi:10.56/NEJM2793401
21. Hill GR, Harrison-Woolrych M. Clozapine and myocarditis:
a case series from the New Zealand Intensive Medicines Monitoring
Programme. N Z Med J. 2008;121(1283):68–75.PubMed
22. Friedrich MG, Strohm O, Schulz-Menger J, et al. Contrast mediaenhanced magnetic resonance imaging visualizes myocardial changes
in the course of viral myocarditis. Circulation. 1998;97(18):1802–1809.PubMed
23. Berk M, Fitzsimons J, Lambert T, et al. Monitoring the safe use of
clozapine: a consensus view from Victoria, Australia. CNS Drugs.
2007;21(2):117–127.PubMed doi:10.265/3-710
24. Devarajan S, Kutcher SP, Dursun SM. Clozapine and sudden death.
Lancet. 2000;355(9206):841, author reply 843.PubMed doi:10.6/S4-73()05
25. Ray WA, Chung CP, Murray KT, et al. Atypical antipsychotic drugs and
the risk of sudden cardiac death. N Engl J Med. 2009;360(3):225–235.PubMed doi:10.56/NEJMa894
J Clin Psychiatry